Phase 1 study of oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859), in Japanese women with ER-positive and HER2-negative advanced breast cancer (AMEERA-2).

BACKGROUND: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer. METHODS: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed. RESULTS: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported. CONCLUSIONS: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer. TRIAL REGISTRATION: Clinical trial registration NCT03816839.

Bioadhesive polymer/lipid hybrid nanoparticles as oral delivery system of raloxifene with enhancive intestinal retention and bioavailability.

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator used to treat osteoporosis in postmenopausal women. RLX fails to be developed into injectable dosage forms due to poor solubility. Although oral formulations are clinically available, the lower bioavailability (<2%) embarrasses the pharmaceutists. This work reported a bioadhesive nanosystem intended for oral delivery of RLX to enhance its oral bioavailability and address the formulation challenge. The bioadhesive nanosystem refers to polymer-lipid hybrid nanoparticles made up of Carbopol 940, glyceryl distearate, and TGPS. RLX was solidly encapsulated into bioadhesive nanoparticles (bNPs) through a nanoprecipitation technique along with synchronous desalting of RLX·HCl. The resultant RLX-loaded bNPs (RLX-bNPs) were characterized by particle size, ζ potential, morphology, and entrapment efficiency. The in vitro release and in vivo oral bioavailability of RLX-bNPs in rats were comparatively investigated with RLX-loaded common lipid nanoparticles (RLX-cNPs). The preferred formulation possesses a particle size of 150 nm around with a polydispersity index (PDI) of 0.282. RLX-bNPs exhibited slower drug release than RLX-cNPs owing to the presence of an adhesive layer. After oral administration, RLX-bNPs resulted in significant enhancement in the bioavailability of RLX, up to 556.9% relative to RLX suspensions, while it was merely 244.7% for RLX-cNPs. Cellular testing and ex vivo transport imaging demonstrated that bNPs were endowed with excellent intestinal epithelial affinity and absorbability. Our study affords an alternative option for designing a suitable oral delivery system specific to amphiphobic drugs like RLX·HCl.

Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging.

BACKGROUND: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17ß-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). METHODS: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. RESULTS: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. CONCLUSION: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02650817 . Registered on 08 January 2016.

Nanostructured lipid carrier potentiated oral delivery of raloxifene for breast cancer treatment.

Nanotherapeutics in cancer treatment are dominating global science and research, and have been recognized as the pioneering medical care regimen. Raloxifene (RLN) has been used for its anti-proliferative action on mammary tissue, however, it suffers from poor oral bioavailability. This investigation gives an account of the design and development of RLN-loaded nanostructured lipid carriers (RLN-NLCs) using a simple and scalable ultrasonication method for improved oral efficacy and limited offsite toxicity using Compritol® 888 ATO as a solid lipid and Transcutol® HP as a liquid lipid. In addition, the optimized RLN-NLCs were in the nanometric range (121 nm) with high % entrapment efficiency (%EE) (81%) for RLN, and were further freeze-dried in the presence of mannitol to enhance the stability of RLN-NLCs in the dry state for long-term use. Morphological observation under a transmission electron microscope and scanning electron microscope revealed the spherical smooth surface nanometric size of RLN-NLCs. Powder x-ray diffraction confirmed the encapsulation of RLN into the RLN-NLC's matrix with reduced crystallinity of the drug. The in vitro release study showed a burst release for an initial 4 h, and sustained release for up to 24 h. Furthermore, the RLN-NLCs showed higher cytotoxicity towards MCF-7 cells in vitro in comparison to RLN suspension, and an ex vivo intestinal permeation study demonstrated improved intestinal permeability of RLN-NLCs. Moreover, the in vivo pharmacokinetic study in female Wistar rats showed a 4.79-fold increment in oral bioavailability of RLN from RLN-NLCs compared to RLN suspension. Taken together, our results pave the way for a new nanotherapeutic approach towards breast cancer treatment.

Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women.

BACKGROUND AND OBJECTIVES: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. METHODS: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. RESULTS: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. CONCLUSIONS: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile.

A matrix dispersion based on phospholipid complex system: preparation, lymphatic transport, and pharmacokinetics.

Raloxifene hydrochloride (RH) suffers from low oral bioavailability due to its low water-solubility and first-pass metabolism. Therefore, a novel phospholipid complex of RH (RHPC) and a matrix dispersion based on phospholipid complex (RHPC-MD) were successfully prepared and optimized. Several methods were used to validate the formation of RHPC and RHPC-MD, such as differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, infrared spectroscopy, particle size, and zeta potential, meanwhile, their octanol-water partition coefficient, solubility, and dissolution in vitro were also evaluated. To investigate the absorption mechanism of RHPC in vivo, the RHPC was administered to the chylomicron flow blockage rat model. Interestingly, as we expected, a significant reduction in RHPC absorption (67%) (**p< .01) in presence of cycloheximide (CXI) inhibitor was observed, thus confirming the RHPC could be absorbed by lymphatic transport in vivo. Pharmacokinetic studies revealed that the relative oral bioavailability of RHPC as well as RHPC-MD was 223% and 329%, respectively, when comparing with the commercial RH tablets. These outcomes suggested that the current study provided an attractive formulation to enhance the oral bioavailability of RH and stimulated to further research the absorption mechanism of RHPC in vivo.

Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer.

More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.

Pulmonary delivery alters the disposition of raloxifene in rats.

OBJECTIVE: Pulmonary delivery is an effective way to improve the bioavailability of drugs with extensive metabolism. This research was designed to study the different pharmacokinetic behaviours of small molecule drug after pulmonary delivery and intragastric (i.g) administration. METHODS: Raloxifene, a selective estrogen receptor modulator with low oral bioavailability (~2%), was chosen as the model drug. Studies were conducted systematically in rats, including plasma pharmacokinetics, excretion, tissue distribution and metabolism. KEY FINDINGS: Results showed that raloxifene solution dosed by intratracheal (i.t) administration exhibited relatively quick plasma elimination (t1/2  = 1.78 ± 0.14 h) and undetected absorption process, which was similar with intravenous injection. Compared with i.g administration, the bioavailability increased by 58 times, but the major route of excretion remained faecal excretion. Drug concentration on the bone and the target efficiency were improved by 49.6 times and five times, respectively. Benefited from quick elimination in the lung, chronic toxicity might be ignored. CONCLUSIONS: Pulmonary administration improved the bioavailability of raloxifene and further increased the distribution on the target organ (bone), with no obvious impact on its excretory pattern.

Vitamin E TPGS based transferosomes augmented TAT as a promising delivery system for improved transdermal delivery of raloxifene.

Raloxifene is commonly used for breast cancer protection. The low bioavailability of raloxifene (2%) is the result of its low solubility and intestinal glucuronidation. The nano-lipid carriers are characterized by small particle size, biocompatibility, and sustainable properties that improve cellular uptake of the loaded drug. The aim of this study was the improvement of raloxifene bioavailability by enhancing its solubility and cellular penetration through formulation of D-α-tocopheryl polyethylene glycol 1000 succinate based transferosomes and augmenting their effect with the cationic cell-penetrating peptide transactivator of transcription of the human immunodeficiency virus. Particle size, zeta potential, and transmission electron microscope investigation of the formed nanocarriers were carried out. Ex vivo raloxifene permeation through rat skin and cell viability studies was investigated. The results of D-α-tocopheryl polyethylene glycol 1000 succinate- transactivator of transcription of the human immunodeficiency virus transferosomes showed an average vesicle size of 96.05 nm with positively charged vesicles 39.4 mV of zeta potential value. The results revealed significant (p < 0.05) enhancement of raloxifene permeation from raloxifene transferosomes- loaded film when compared with raw raloxifene film. IC50 results showed significant improvement of formulated raloxifene cytotoxicity by 1.42-fold in comparison with raw raloxifene against MCF-7 cell lines. The developed raloxifene-transferosomes are considered promising nano-lipid carriers for the enhancement delivery of raloxifene.

Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer.

The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing ESR1 mutations. A novel 3-oxyazetidine side chain was designed, leading to 37d, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.

Tissue Distribution and Systemic Toxicity Evaluation of Raloxifene Targeted Polymeric Micelles of Poly (Styrene-Maleic Acid)-Poly (Amide- Ether-Ester-Imide)-Poly (Ethylene Glycol) Loaded With Docetaxel in Breast Cancer Bearing Mice.

BACKGROUND: Due to the low water solubility of Docetaxel (DTX), it is formulated with ethanol and Tween 80 with lots of side effects. For this reason, special attention has been paid to formulate it in new drug nano-carriers. OBJECTIVE: The goal of this study was to evaluate the safety, antitumor activity and tissue distribution of the novel synthesized Raloxifene (RA) targeted polymeric micelles. METHODS: DTX-loaded RA-targeted polymeric micelles composed of poly(styrene-maleic acid)- poly(amide-ether-ester-imide)-poly(ethylene glycol) (SMA-PAEE-PEG) were prepared and their antitumor activity was studied in MC4-L2 tumor-bearing mice compared with non-targeted micelles and free DTX. Safety of the micelles was studied by Hematoxylin and Eosin (H&E) staining of tumors and major organs of the mice. The drug accumulation in the tumor and major organs was measured by HPLC method. RESULTS: The results showed better tumor growth inhibition and increased survival of mice treated with DTX-loaded in targeted micelles compared to the non-targeted micelles and free DTX. Histopathological studies, H&E staining of tumors and immunohistochemical examination showed the potential of DTX-loaded RA-targeted micelles to inhibit tumor cells proliferation. The higher accumulation of the DTX in the tumor tissue after injection of the micelles compared to the free DTX may indicate the higher uptake of the targeted micelles by the G-Protein-Coupled Estrogen Receptors (GPER). CONCLUSION: The results indicate that RA-conjugated polymeric micelles may be a strong and effective drug delivery system for DTX therapy and uptake of the drug into tumor cells, and overcome the disadvantages and side effects of conventional DTX.

Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer.

BACKGROUND: An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers. METHODS: The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities. RESULTS: Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks. CONCLUSION: TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

In situ misemgel as a multifunctional dual-absorption platform for nasal delivery of raloxifene hydrochloride: formulation, characterization, and in vivo performance.

BACKGROUND: Raloxifene hydrochloride (RLX) is approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis, in addition to reducing the risk of breast cancer in postmenopausal women. RLX has the disadvantages of low aqueous solubility, extensive presystemic intestinal glucuronidation, and first-pass metabolism, resulting in a limited bio-availability of only 2%. The aim of this work was to enhance the bioavailability of RLX via the formulation of an in situ nasal matrix (misemgel) comprising micelles made of vitamin E and D-α-tocopheryl polyethylene glycol 1000 succinate and nanosized self-emulsifying systems (NSEMS). MATERIALS AND METHODS: Optimization of the RLX-loaded NSEMS was performed using a mixture design. The formulations were characterized by particle size and then incorporated into an in situ nasal gel. Transmission electron microscopy, bovine nasal mucosa ex vivo permeation, and visualization using a fluorescence laser microscope were carried out on the RLX in situ misemgel comparing with raw RLX in situ gel. In addition, the in vivo performance was studied in rats. RESULTS: The results revealed improved permeation parameters for RLX misemgel compared with control gel, with an enhancement factor of 2.4. In vivo studies revealed a 4.79- and 13.42-fold increased bioavailability for RLX in situ misemgel compared with control RLX in situ gel and commercially available tablets, respectively. The obtained results highlighted the efficacy of combining two different formulations to enhance drug delivery and the benefits of utilizing different possible paths for drug absorption. CONCLUSION: The developed in situ misemgel matrix could be considered as a promising multifunctional platform for nasal delivery which works based on a dual-absorption mechanism.

Assessment of the Effects of Age and Renal Function on Pharmacokinetics of Bazedoxifene in Postmenopausal Women.

Bazedoxifene (BZA), a chemically distinct selective estrogen receptor modulator, has demonstrated efficacy and long-term safety in phase 3 placebo-controlled studies for prevention and treatment of osteoporosis. Here, we assessed the potential effects of age and renal function on BZA pharmacokinetics in healthy postmenopausal women (aged 55-84 years; CLcr, 32-109 mL/min). This was an open-label, single-dose, parallel, nonrandomized inpatient study conducted in healthy postmenopausal women and postmenopausal women with impaired renal function. Each subject received a single oral dose of BZA in a 20-mg tablet. Twenty-six subjects were enrolled: 8 in each of 3 age groups (55-64 years, 65-74 years, ≥75 years) and 2 (aged 71 and 75 years) with mild renal impairment; all subjects received treatment and completed the study. Age-related changes in pharmacokinetics were apparent. Although the correlation was modest (R2 = 0.28), BZA CL/F decreased steadily with age, such that the oldest group (>75 years) had a mean CL/F 60% less than the youngest group (55-64 years). Over the observed range of CLcr, there was a weak positive correlation (R2 = 0.19) between BZA CL/F and CLcr.

A Study of the Potential Interaction Between Bazedoxifene and Atorvastatin in Healthy Postmenopausal Women.

An open-label, 3-period study was conducted in 30 healthy postmenopausal women (mean age, 58.4 years) who received a single oral dose of atorvastatin 20 mg on day 1 (period 1), multiple daily dosing of bazedoxifene 40 mg on days 4-11 (period 2), and coadministration of atorvastatin 20 mg + bazedoxifene 40 mg on day 12 (period 3). Serial blood samples were collected (24 hours after bazedoxifene and 72 hours after atorvastatin) and assayed for bazedoxifene, atorvastatin, and its ortho-hydroxy and para-hydroxy metabolites. Pharmacokinetic parameters were calculated using noncompartmental methods. Bazedoxifene exposure was not altered with coadministration of atorvastatin 20 mg (Cmax and AUCss were within bioequivalence limits). Similarly, atorvastatin and ortho-hydroxyatorvastatin exposure was equivalent with or without coadministration with bazedoxifene. Para-hydroxyatorvastatin concentrations were below the limit of quantitation under both conditions. Cmax for atorvastatin and ortho-hydroxyatorvastatin was 14% and 18% lower, respectively, and Tmax was 20% and 34% longer, respectively, with the combination compared with atorvastatin alone. There were no serious adverse events, and no subjects discontinued the study because of safety. No clinically significant pharmacokinetic interaction was observed between bazedoxifene and atorvastatin or its active metabolites, indicating they may be safely coadministered without dosage adjustment.

Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation.

Raloxifene HCl belongs to a class of selective estrogen receptor modulators (SERMs) which is used for the management of breast cancer. The major problem reported with raloxifene is its poor bioavailability which is only up to 2%. The main objective of the present work was to formulate raloxifene loaded ethosomal preparation for transdermal application and compare it with an oral formulation of the drug. Five ethosomal formulations with different concentrations of ethanol and a conventional liposomes formulation were prepared by rotary evaporation method. The prepared systems were characterised by high resolution transmission electron microscopy (HRTEM), force emission electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and 31P NMR study. All these advanced characterization study established that the ethosome formulation was well defined by its size, shape and its bilayer formation. Transdermal flux of the optimized ethosome formulation was 22.14 ±â€¯0.83 µg/ml/cm2 which was 21 times higher when compared to the conventional liposomes. Confocal microscopy study revealed an enhanced permeation of coumarin-6 dye loaded ethosomes to much deeper layers of skin when compared with conventional liposomes. The gel was found to be pseudoplastic with elastic behaviour. In-vivo studies on rats showed a higher bioavailability of RXL (157% times) for ethosomal formulation when compared with the oral formulation. In conclusion, RXL loaded ethosomal formulation via transdermal route showed superior drug delivery properties as compared to oral formulation.

Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites.

Clomiphene citrate, a selective estrogen receptor modulator, is metabolized into its 4-hydroxylated active metabolites, primarily by CYP2D6. In this study, we investigated the effects of the most common CYP2D6 variant allele in Asians, CYP2D6*10, on the pharmacokinetics of clomiphene and its two active metabolites (4-OH-CLO and 4-OH-DE-CLO) in healthy Korean subjects. A single 50-mg oral dose of clomiphene citrate was given to 22 Korean subjects divided into three genotype groups according to CYP2D6 genotypes, CYP2D6*wt/*wt (n = 8; *wt = *1 or *2), CYP2D6*wt/*10 (n = 8) and CYP2D6*10/*10 (n = 6). Concentrations of clomiphene and its metabolites were determined using a validated HPLC-MS/MS analytical method in plasma samples collected up to 168 h after the drug intake. There was a significant difference only in the Cmax of clomiphene between three CYP2D6 genotype groups (p < 0.05). Paradoxically, the elimination half-life (t1/2) and AUC of both active metabolites were all significantly increased in the CYP2D6*10 homozygous carriers, compared with other genotype groups (all p < 0.001). The AUCinf of corrected clomiphene active moiety in CYP2D6*10/*10 subjects was 2.95- and 2.05-fold higher than that of CYP2D6*wt/*wt and *wt/*10 genotype groups, respectively (both p < 0.001). Along with the partial impacts on the biotransformation of clomiphene and its metabolites by CYP2D6 genetic polymorphism, further studies on the effects of other CYP enzymes in a multiple-dosing condition can provide more definite evidence for the inter-individual variabilities in clomiphene pharmacokinetics and/or drug response.

Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.

Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial.

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS).Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor-positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS.Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per µg/L increase in endoxifen (95% confidence interval, 0.971-1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS.Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312-8. ©2018 AACR.